A follicle is a nonspecific conjunctival response to chronic irritation: mechanical, chemical, or microbial. Conjunctival follicles do not appear in the neonatal period because the lymphoid system is immature, and they are less apparent in children under the age of 2. After the first few weeks of life, lymphoid tissue becomes evident in the human conjunctiva, with a diffuse and indiscriminate distribution. Under the influence of chronic irritation or stimulation, the lymphocytes increase and aggregate into follicles resembling, in structure and function, the lymph nodes or the solitary lymphatic patches of the intestine.1, 2

Clinically, follicles are yellowish to grayish white, discrete, round elevations of the conjunctiva. The central part of the follicle is avascular, but dilated blood vessels may surround the base and sweep up from the base over the convexity (Fig. 7.1). Follicles are 0.2 to 2 mm in size, although larger follicles may be seen, particularly in chlamydial disease.3 They can be seen with the naked eye, but with the slit lamp their apex looks a bit pale as the conjunctival vessels are blanched due to the pressure of lymphoid accumulation in a small space.

Follicles on the superior tarsal conjunctiva are well defined as a result of the close adherence of the tarsus to the epithelial mucosal tissues. They are also seen in the conjunctival fornices, where they are less regularly spaced and tend to be larger (Figs. 7.2 and 7.3). Histologically, follicles consist of lymphoid germinal centers with fibroblasts in the center. T cells occupy the periphery, and B cells the center of the infiltrates.4

Follicles are often clinically confused with conjunctival papillae (Fig. 7.4). Papillae are vascular changes most prominent on the palpebral conjunctiva, where fibrous septa anchor the conjunctiva to the underlying tarsus. In contrast to follicles, they are small flat projections of the conjunctiva with a dilated vascular core (with side branches along the way) surrounded by edema and a mixed inflammatory infiltrate producing raised elevations of the conjunctival epithelium. The presence of the central core of blood vessel (cf. follicle with blanched apex) and tabloid shape distinguish it from the follicles (Fig. 7.5). They are nonspecific signs of conjunctival inflammation, most commonly associated with allergic or bacterial conjunctivitis.

Follicular conjunctivitis is not a specific disease entity, but a connotation for a large number of conditions of varying etiologies that have follicles as a predominant pathologic and clinical manifestation.

Adenoviruses are double-stranded DNA viruses surrounded by a nonenveloped polypeptide icosahedral capsid with glycoprotein projections. They were first detected in 1953 as a latent virus in surgically removed adenoidal tissue from asymptomatic children.5 There are at least 52 serotypes of adenovirus, and they have been classified into seven species, A to G, on the basis of their hemagglutination properties and biophysical and biochemical criteria.6 In addition, recently two more serotypes, Ad 53 and 54, have been identified to cause Epidemic keratoconjunctivitis (EKC) in Japan.7 Most of the recently described serotypes (42 to 49, 51) belong to species D and were first isolated from human immunodeficiency virus (HIV)-infected patients. Adenoviruses are a common cause of a variety of human illnesses, accounting for approximately 10% of all febrile illnesses in infants and 5% of all such illnesses in children.8

Ocular adenoviral infections have a variety of clinical presentations; the two most common forms are EKC and pharyngoconjunctival fever (PCF). Both are characterized by a marked follicular response. Two less common manifestations are nonspecific sporadic follicular conjunctivitis and chronic papillary conjunctivitis.

The different syndromes tend to be caused by distinct serotypes, although the features do overlap. Most of the keratoconjunctivitis and all of the epidemic keratoconjunctivitis types are caused by species D; however, serotype 4, the only included species E, is also known to cause conjunctivitis.6 Ad 3 and Ad 4 are the most common pathogens that cause sporadic keratoconjunctivitis and PCF. Ad 4, 8, 19, and 37 have been implicated in sporadic cases as well as outbreaks of severe EKC.9, 10, 11 and 12 Although an epidemic due to both types 8 and 19 has been reported, most disease is due to a single serotype.

At least 21 documented serotypes cause EKC. The most commonly associated serotypes include adenovirus 8, 19, and 37, and, less frequently, serotypes 2-5, 7, 9-11, 14, 16, 21, 29, 53, and 54.6, 7 The clinical features of adenoviral keratoconjunctivitis were first described by Fuchs in 1889,13 but it was not until 1955 that adenovirus was identified as the cause of the disease.14 The natural level of immunity against adenoviruses is low in the general population, and therefore every individual is susceptible.

Adenovirus is highly contagious, and measures to limit the spread of infection should be taken. Spread is by person-to-person contact, contaminated ophthalmic instruments, or swimming water. Transmission in ophthalmology clinics has been well reported, most frequently as a result of applanation tonometry; however, slit lamp examination and application of eye drops may also result in spread, emphasizing the need for adherence to strict hand-washing protocols.10, 15, 16 In Asia, however, EKC is endemic and does not appear to be transmitted through medical intervention.

EKC has a wide spectrum of duration and intensity of symptoms. After an incubation period of 2 to 14 days, symptoms begin in one eye; symptoms develop in the second eye 2 to 4 days later. Signs include conjunctival hyperemia and chemosis, intense tearing, and swelling of the conjunctival plica. Ipsilateral preauricular lymphadenopathy is found in many patients. The corneal involvement helps distinguish it from other causes of viral conjunctivitis (Figs. 7.8 and 7.9).

Corneal epithelial involvement is noted 2-4 days after the onset of symptoms and takes the form of diffuse fine epithelial keratitis and may stain with fluorescein and rosebengal. The epithelial keratitis may persist for 2 to 3 weeks. About a week after the onset of symptoms, larger nummular lesions develop. These have irregular, raised borders and a central ulceration that stains with both fluorescein. At 2 weeks, the subepithelial infiltrates (SEIs) begin to appear underneath the focal epithelial lesions. These infiltrates consist of lymphocytes, histiocytes, and fibroblasts accompanied by a disruption of the collagen fiber of Bowman layer.17 The nummular opacities are thought to represent persisting viral replication in subepithelial keratocytes, triggering a host reaction. The immune basis is supported by the clinical observation that the opacities usually resolve with topical steroids, but recur when the steroids are discontinued.18 Rarely, these nummular opacities or infiltrates may impair visual function and may persist for months or years. Usually, the conjunctival inflammation and epithelial disease resolve in 10 to 16 days, but may last up to a month. The follicles and lymphadenopathy resolve more gradually in 2 to 4 weeks; however, the SEIs may persist for many months. EKC is also the commonest cause of viral membranous or pseudomembranous conjunctivitis (Fig. 7.10).

Adenoviruses also produce the classic triad of fever, pharyngitis, and acute follicular conjunctivitis in PCF. PCF occurs more commonly in children, and is spread by respiratory secretions. It is caused by serotypes 3 and 7, but serotypes 2, 4, and 14 have also been documented as etiological agents. In addition, sporadic outbreaks caused by serotypes 1, 5, 6, 8, 11, and 19 have been reported.25, 26 and 27 The symptoms are similar to EKC, with tearing and foreign body sensation that is initially unilateral. The follicular conjunctivitis produces a watery discharge with associated preauricular or submandibular lymphadenopathy, and occasional petechial hemorrhages. Although corneal involvement is not a key feature, there is occasionally a punctate keratitis; however, SEIs are rare. PCF is a selflimiting condition that varies in severity and may last from 4 days to 2 weeks. The virus remains in the conjunctiva for 2 weeks, but fecal excretion can last a month.27 Treatment is symptomatic, and topical steroids are rarely needed.

It is actually a very mild form of conjunctivitis and consequently usually seen in the physician’s office. It can occur in any of the serotypes of adenoviruses that can cause EKC or PCF. It resolves spontaneously over 7 to 10 days without any sequelae. It is endemic and actually serves as a reservoir for more severe outbreaks.28

Childhood rubella is often accompanied by a catarrhal conjunctivitis and sometimes a mild follicular conjunctivitis. In around 2% of cases, approximately 1 week after the appearance of rash, there may be a mild superficial punctate keratitis in the central cornea associated with photophobia and tearing.41 The acute disease usually resolves spontaneously without leaving any sequelae.42

Primary herpes simplex infection is frequently associated with blepharitis and a vesicular lesion on the lid margin, a clinical feature that aids diagnosis. It typically occurs in children and may have associated upper respiratory symptoms and stomatitis. Half of all primary HSV infections involving the lid margin will develop corneal epithelial manifestations ranging from fine punctate epithelial staining to dendritic ulceration.54, 55 However, frank geographical keratitis has also been reported in primary infection.56 In primary herpetic eye disease, the ulceration is more commonly fine microdendrites involving the cornea and conjunctiva, unlike the prominent dendrites in recurrent disease.

The incidence of HSV ocular infection presenting as acute follicular conjunctivitis in the absence of corneal or lid signs in cases of clinically diagnosed epidemic keratoconjunctivitis is 1.3% to 7%.57, 58 The clinical features of primary and recurrent HSV conjunctivitis are quite similar.59 The corneal changes are rare, and it is bilateral in 13% of cases.59 It has a mean duration of 8 days. The low rate of bilateral disease and the short duration may help discriminate HSV from adenoviral conjunctivitis, as clinically differentiating the two disease entities is extremely difficult, particularly in the early stages.

Most herpetic infections of the eye are caused by human herpesvirus type 1 (oral); however, type 2 (genital) may occur in the newborn and adults after oral-genital inoculation. Neonates who develop herpes simplex primary conjunctivitis should receive intravenous treatment with acyclovir in addition to topical treatment.

The Herpetic Eye Disease Study (HEDS) assessed whether long-term prophylactic treatment with acyclovir would prevent recurrence of ocular herpetic disease.60 This was a prospective randomized, multicenter trial, and although it did not primarily address herpetic conjunctivitis, its findings did suggest that the use of 800 mg (or 400 mg b.i.d.) oral acyclovir daily over a year reduced the recurrence of ocular herpetic disease.

Cytomegalovirus (CMV) infection in otherwise healthy individuals can cause follicular conjunctivitis.61 CMV is a common cause of chorioretinitis in immunocompromised hosts, and in these patients occasionally conjunctivitis is seen.62

Epstein-Barr virus (EBV), a ubiquitous DNA herpesvirus, is the most common causative agent of infectious mononucleosis syndrome. Ocular manifestations include a follicular or membranous conjunctivitis with or without subconjunctival hemorrhages.63, 64 Discrete granular subepithelial infiltrates may be seen, with overlying punctate epithelial keratitis.65 The treatment of EBV-associated ocular disease is not defined because of the small number of documented cases. Other ocular complications include uveitis, choroiditis, retinitis, papillitis, and ophthalmoplegia.63

The disease affects initially one eye, 1 to 2 weeks after exposure to the organism. The symptoms may be acute or subacute, with redness, irritation, and a mucopurulent discharge. A palpable, nontender preauricular node may develop, but there are no systemic symptoms. Most of the conjunctival findings are located inferiorly, with a predominantly follicular reaction also associated with some degree of papillary reaction (Fig. 7.11). Limbal swelling is also often present.

Pseudomembranes do not occur, and conjunctival scarring, if it does occur, is minimal. In the second week, the cornea may have a mild or moderate superficial punctate keratitis that may be fine or coarse. Later in the infection, peripheral epithelial or subepithelial infiltrates may occur, which have an intact epithelium. Occasionally, iritis will occur in the later stages and, rarely, Reiter’s syndrome. A superficial micropannus may develop in those who had subepithelial infiltrates, but there is no frank corneal scarring.

After a detailed history and clinical examination a fluorescent monoclonal antibody test is the most sensitive method of rapid diagnosis.74 Giemsa-stained conjunctival smears looking for perinuclear inclusion bodies have a high false-negative rate75 (Fig. 7.12). In recent years, polymerase chain reaction (PCR) assay has become more widely used as an effective diagnostic tool to accurately detect the presence of chlamydial material in ocular specimens (see section on “Laboratory Diagnosis”).

Patients and their partners should be screened for nonocular chlamydial infection and for other venereal diseases. Systemic treatment is mandatory. The recommended treatment for chlamydial infection is azithromycin 1 g as a single daily dose for 7 days, or doxycycline 100 mg twice daily for 7 days. Alternative regimes are erythromycin 500 mg four times a day for 7 days, or ofloxacin 300 mg twice a day for 7 days.76

Trachoma is an ancient disease and remains the most common cause of chronic follicular conjunctivitis and the foremost cause of blindness worldwide after cataract.82 It is the most common cause of preventable blindness. Trachoma was described in the Egyptian Ebers papyrus in 1900 BC and remains endemic to that country. It was endemic in Europe into the 20th century. Would-be immigrants to the United States were screened for trachoma on arrival at Ellis Island, and those with the characteristic follicles were turned away.

Trachoma has disappeared from Western Europe and North America as a result of improved living conditions. However, trachoma continues to affect 150 million people in 48 countries, of which 6 million are blind.82 In areas where trachoma is constantly present at high prevalence, active disease is found in more than 50% of preschool children. As many as 75% of women and 50% of men over the age of 45 may show signs of scarring disease.83 Infected children are the major reservoir for trachomatous infection in a community.84, 85 The prevalence of active trachoma decreases with increasing age, with less than 5% of adults showing signs of active disease. Although similar rates of active disease are observed in male and female children, the later sequelae of trichiasis, entropion, and corneal opacification are more common in women than men.86 This is probably related to the close contact of women with children who are suffering from the active disease.